2-232087546-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152383.5(DIS3L2):c.426C>T(p.Pro142=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,892 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 31)
  • Exomes 𝑓: 0.014 (194 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.54

Genes affected

DIS3L2 (HGNC:28648): (DIS3 like 3'-5' exoribonuclease 2) The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-232087546-C-T is Benign according to our data. Variant chr2-232087546-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232087546-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1720/152042) while in subpopulation NFE AF= 0.0164 (1117/67982). AF 95% confidence interval is 0.0156. There are 19 homozygotes in gnomad4. There are 859 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.426C>T	p.Pro142=	synonymous_variant	6/21	ENST00000325385.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.426C>T	p.Pro142=	synonymous_variant	6/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1723 AN: 151924 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.0113 AC: 2817 AN: 249502 Hom.: 29 AF XY: 0.0111 AC XY: 1500 AN XY: 135348

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0138 AC: 20131 AN: 1461850 Hom.: 194 Cov.: 31 AF XY: 0.0135 AC XY: 9785 AN XY: 727216

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00438

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00222

Gnomad4 SAS exome AF: 0.00434

Gnomad4 FIN exome AF: 0.0288

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0113 AC: 1720 AN: 152042 Hom.: 19 Cov.: 31 AF XY: 0.0116 AC XY: 859 AN XY: 74320

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0278

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.00999

Alfa AF: 0.0143 Hom.: 16

Bravo AF: 0.00881

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Perlman syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.32
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73001172; hg19: chr2-232952256;